While a number of recent studies have focused on the role of stromal cells in advanced carcinomas, the[unreadable] stromal changes contributing to carcinogenesis have received considerably less attention. Gastric and[unreadable] hepatocellular cancer are two of the leading causes of cancer mortality worldwide, and are strongly linked to[unreadable] chronic infection (H. pylori versus HBV/HCV, respectively) and the consequent state of sustained[unreadable] inflammation. This application is submitted by the Tumor Microenvironment Program at the Columbia[unreadable] University Cancer Center, bringing together leading investigators in the areas of gastric carcinogenesis and[unreadable] liver fibrosis with experts in other areas to examine the role of stromal cells in liver and gastric[unreadable] carcinogenesis. This highly collaborative and multidisciplinary group encompasses experts in stromal cells,[unreadable] chronic inflammation/NF-kB, angiogenesis, epigenetics, optical imaging, and bioinformatics. It also includes[unreadable] a clinical arm that will conduct parallel studies on stromal cells from primary gastric and liver tumors, and a[unreadable] translational component (effects of COX-2 inhibition on tumor vascular stromal cells). Our proposal is based[unreadable] heavily on novel observations by this team of researchers regarding the bone marrow origin of cancer and[unreadable] stromal cells, the mechanism of activation of myofibroblasts (e.g. stellate cells), and on the link between[unreadable] chronic inflammation, angiogenesis, and the development of cancer. The program includes 4 projects and 2[unreadable] cores.[unreadable] Project 1. Stromal myofibroblasts in gastric carcinogenesis (PI - Timothy C. Wang).[unreadable] Project 2. Stromal myofibroblasts in hepatic carcinogenesis (PI - David A. Brenner)[unreadable] Project 3. Interactions between digestive cancers and the vascular stroma (PI - Jan Kitajewski)[unreadable] Project 4. Epigenetics and genetics of stromal cells in liver and gastric cancer (PI - Benjamin Tycko)[unreadable] The Cores, which include an Imaging Core led by Andreas Hielscher, and an Administrative/Bioinformatics[unreadable] Core led by Timothy C. Wang and Andrea Califano, will be utilized by most of the projects and will provide[unreadable] additional focus and unity to the Project as a whole. In addition, most of the projects will utilize unique[unreadable] transgenic models of cancer (e.g. INS-GAS), reporter gene mice (ASMA-RFP/COLL-EGFP/Luc) targeting[unreadable] myofibroblasts, and a new method of methylation-sensitive SNP chip analysis (MSNP) to profile the[unreadable] myofibroblasts. Taken together, the data from these murine and human studies should lead to new insights[unreadable] regarding tumor-stroma interactions and their origins in early cancer.[unreadable]